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Research
Yongjun Zhou
Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3005-2843
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Neoantimycins are a group of 15-membered ring depsipeptides isolated from streptomycetes with a broad-spectrum of anticancer activities. Their biosynthesis is directed by the hybrid multimodular megaenzymes of non-ribosomal peptide synthetase and polyketide synthase. We have previously discovered a new neoantimycin analogue unantimycin B, which was demonstrated with selective anticancer activities and was produced from neoantimycins biosynthetic pathway with a starter unit of 3-hydroxybenzoate, instead of the 3-formamidosalicylate for neoantimycins. However, the low fermentation yield and tough isolation procedure have been hindering in-depth pharmacology investigation of unantimycin B as anticancer agents.
Results
In the work, we genetically constructed two unantimycin B producer strains with neoantimycins production destroyed by removing natO and natJ-L genes essential for 3-formamidosalicylate biosynthesis and therefore facilitated chromatographic separation of unantimycin B from the complex fermentation extract. Based on the △natO mutant, we improved unantimycin B
production by two times, reaching to approximate 12.8 mg/L, by feeding 3-hydroxybenzoate in fermentation. Further, the production was improved by more than six times, reaching to approximate 40.0 mg/L, in the △natO strain introduced with a chorismatase gene highly expressed under a strong promoter for over-producing 3-hydroxybenzoate endogenously.
Conclusion
The work gives a case of targeting accumulation and significant production improvement of medicinally interesting natural products via genetically manipulation of precursor biosynthesis in streptomycetes, the talented producers of pharmaceutical molecules.
Keywords
anticancer, depsipeptides, natural products biosynthesis, 3-hydroxybenzoate, 3-formamidosalicylate, chorismic acid
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CURRENT STATUS: Under Review
Version 1
Posted 04 Mar, 2021
No community comments so far
Editorial decision: Major revision
On 26 Mar, 2021
Review #3 received
Received 23 Mar, 2021
Review #2 received
Received 23 Mar, 2021
Review #5 received
Received 21 Mar, 2021
Review #4 received
Received 21 Mar, 2021
Review #1 received
Received 19 Mar, 2021
Reviewer #4 agreed
On 17 Mar, 2021
Reviewer #5 agreed
On 17 Mar, 2021
Reviewer #3 agreed
On 17 Mar, 2021
Reviewer #2 agreed
On 03 Mar, 2021
Reviews received
Received 02 Mar, 2021
Reviewers invited
Invitations sent on 02 Mar, 2021
Reviewer #1 agreed
On 02 Mar, 2021
Editor assigned
On 26 Feb, 2021
Editor invited
On 26 Feb, 2021
Submission checks complete
On 26 Feb, 2021
First submitted
On 22 Feb, 2021
Metrics
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Subject Areas
Biotechnology and Bioengineering
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A new preprint design is coming!
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This preprint is under consideration at Bioresources and Bioprocessing. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Yongjun Zhou
Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3005-2843
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 04 Mar, 2021
No community comments so far
Editorial decision: Major revision
On 26 Mar, 2021
Review #3 received
Received 23 Mar, 2021
Review #2 received
Received 23 Mar, 2021
Review #5 received
Received 21 Mar, 2021
Review #4 received
Received 21 Mar, 2021
Review #1 received
Received 19 Mar, 2021
Reviewer #4 agreed
On 17 Mar, 2021
Reviewer #5 agreed
On 17 Mar, 2021
Reviewer #3 agreed
On 17 Mar, 2021
Reviewer #2 agreed
On 03 Mar, 2021
Reviews received
Received 02 Mar, 2021
Reviewers invited
Invitations sent on 02 Mar, 2021
Reviewer #1 agreed
On 02 Mar, 2021
Editor assigned
On 26 Feb, 2021
Editor invited
On 26 Feb, 2021
Submission checks complete
On 26 Feb, 2021
First submitted
On 22 Feb, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Biotechnology and Bioengineering
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Neoantimycins are a group of 15-membered ring depsipeptides isolated from streptomycetes with a broad-spectrum of anticancer activities. Their biosynthesis is directed by the hybrid multimodular megaenzymes of non-ribosomal peptide synthetase and polyketide synthase. We have previously discovered a new neoantimycin analogue unantimycin B, which was demonstrated with selective anticancer activities and was produced from neoantimycins biosynthetic pathway with a starter unit of 3-hydroxybenzoate, instead of the 3-formamidosalicylate for neoantimycins. However, the low fermentation yield and tough isolation procedure have been hindering in-depth pharmacology investigation of unantimycin B as anticancer agents.
Results
In the work, we genetically constructed two unantimycin B producer strains with neoantimycins production destroyed by removing natO and natJ-L genes essential for 3-formamidosalicylate biosynthesis and therefore facilitated chromatographic separation of unantimycin B from the complex fermentation extract. Based on the △natO mutant, we improved unantimycin B
production by two times, reaching to approximate 12.8 mg/L, by feeding 3-hydroxybenzoate in fermentation. Further, the production was improved by more than six times, reaching to approximate 40.0 mg/L, in the △natO strain introduced with a chorismatase gene highly expressed under a strong promoter for over-producing 3-hydroxybenzoate endogenously.
Conclusion
The work gives a case of targeting accumulation and significant production improvement of medicinally interesting natural products via genetically manipulation of precursor biosynthesis in streptomycetes, the talented producers of pharmaceutical molecules.
Figure 1
Figure 2
Figure 3
Figure 4
This is a list of supplementary files associated with this preprint. Click to download.
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